1. Field of the Invention
The present invention relates to thienopyrimidinone derivatives as antagonists that act on metabotropic glutamate receptor subtype 1 to show pharmacological activity against metabotropic glutamate receptor-related diseases, including pain, such as neuropathic pain and migraine, psychiatric diseases, such as anxiety disorder and schizophrenia, urinary incontinence, and neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. The present invention also relates to methods for preparing the compounds, and pharmaceutical compositions containing the compounds as active ingredients.
2. Description of the Related Art
Glutamate is an important excitatory neurotransmitter in the central nervous system. Synaptic stimulation of glutamate is transmitted through the activities of two receptor types: ionotropic glutamate receptors and metabotropic glutamate receptors. The former receptors are ligand-gated cation channels, and the latter receptors are G-protein-coupled receptors (GPCRs). Metabotropic glutamate receptors are divided into three groups on the basis of their structural similarity, pharmacology, and signaling mechanisms. The three groups are further subdivided into a total of eight subtypes according to their splicing variants. The group I receptors are divided into mGluR1 and mGluR5. The subtypes mGluR1 and mGluR5 activate phospholipase C (PLC) via a Gq/11 protein, resulting in release of calcium via phosphoinositide (PI) hydrolysis. The group II receptors (mGluR2 and mGluR3) and the group III receptors (mGluR4, mGluR5, mGluR6, and mGluR7) are negatively coupled to adenyl cyclase (AC) via a Gi/o protein, inhibiting cAMP formation.
Approximately 70 million Americans suffer from pain. The annual medical expenses for pain treatment and related social costs in the United States are estimated to be 100 billion dollars. Neuropathic pain has numerous etiologies and causes complex and chronic pain conditions. A total of about 18 million Americans, including about 4 million Americans suffering from diabetic pain, are afflicted with neuropathic pain. Various neurological diseases including pain, psychiatric diseases and neuritic diseases are associated with glutamate release. mGluR1, a glutamate receptor, is present on the primary afferent nerve terminals and is abundantly distributed in the pain process-related nervous tissues of the CNS. Thus, mGluR1 is reported to be closely associated with the treatment of pain [Annu. Rev. Pharmacol. Toxicol. 1989, 29, 365; Trends Neurosci. 2011, 24, 550; Expert Opin. Ther. Targets 2002, 6, 349; Neuron 1992, 9, 259].
Various experiment results have revealed that mGluR1 antagonism relieves neuropathic pain. It was reported that the injection of selective mGluR1 antibodies relieves allodynia and hyperalgesia in animal models, and the administration of selective mGluR1 antagonists after administration of Group I mGluR agonists to induce spontaneous pain relieves the pain [Prog. Neurobiol. 1999, 59, 55; Neuro-Report 1996, 7, 2743; J. Neurosci. 2001, 21. 3771].
Many efforts have been made to date to develop mGluR1 antagonists. However, there is still a need for mGluR1 antagonists that are selective for mGluR1, have good pharmacokinetic profiles, have good absorption, distribution, metabolism and excretion (ADME) properties, and are effective against metabotropic glutamate receptor-related diseases, including pain, such as neuropathic pain and migraine, psychiatric diseases, such as anxiety disorder and schizophrenia, urinary incontinence, and neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.